Nearly 200 million people in the world, including ~57 million in Bangladesh and ~17 million in the United States (US), are chronically exposed to inorganic arsenic (As), a class I human carcinogen, and are at increased risk of mortality, cancers as well as cardiovascular, pulmonary and other non-malignant disorders. As part of the Columbia University SRP, we established the Health Effects of Arsenic Longitudinal Study (HEALS)?a large prospective cohort study based on individual-level data among a population exposed to a wide range of inorganic As from drinking water in Araihazar, Bangladesh. Over the past 12 years, using a population-based sampling frame, we recruited >24,000 men and women (with >95% response rates) and collected detailed questionnaires, clinical data, and biospecimen samples at baseline recruitment as well as every two years subsequently. Approximately 80% of participants are exposed to water As at low-to moderate doses (0-150 pg/L) with nearly 75% exposed at <100 pg/L. Through a dedicated medical clinic established by Columbia University and The University of Chicago that exclusively serves the HEALS participants, we have also developed an effective mechanism of following the cohort, especially for detecting incidence of respiratory and cardiovascular disorders. In this proposal, with up to 17 years follow-up, we propose to prospectively evaluate the effects of various measures of As exposure and methylation capacity on: i) all-cause, chronic-disease and cancer-related mortalities; ii) incidence of total and subtypes of chronic non-malignant respiratory disease (CNRD) including chronic obstructive pulmonary disease, restrictive lung disease, and pulmonary tuberculosis; iii) incidence of total and subtypes of cardiovascular disease (CVD) including coronary heart disease and stroke and also CVD subclinical marker carotid artery intima-medial thickness; and, finally to identify iv) modifiable host factors that influence these associations. A combination of prospective study designs including cohort and efficient case-cohort studies will be employed to address these specific aims in the most efficient manner. In addition to investigating these novel research questions, as in the previous funding period, the HEALS cohort will continue to support other biomedical research.